title: Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms.
abstract: The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.|Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Brioli
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kaiser
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: Fabio
authors.initials: F
authors.lastname: Mirabella
authors.affiliation: Department of Hematology of the University Hospital of Salamanca; Centro de Investigacion del Cancer (CIC) de Salamanca; and Instituto Biosanitario de Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Lopez-Corral
authors.affiliation: Illumina Cambridge Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Humphray
authors.affiliation: Illumina Cambridge Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Murray
authors.affiliation: Illumina Cambridge Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.affiliation: Illumina Cambridge Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.affiliation: Department of Hematology of the University Hospital of Salamanca; Centro de Investigacion del Cancer (CIC) de Salamanca; and Instituto Biosanitario de Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Norma C
authors.initials: NC
authors.lastname: Gutiérrez
authors.affiliation: Department of Hematology of the University Hospital of Salamanca; Centro de Investigacion del Cancer (CIC) de Salamanca; and Instituto Biosanitario de Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Garcia-Sanz
authors.affiliation: Department of Hematology of the University Hospital of Salamanca; Centro de Investigacion del Cancer (CIC) de Salamanca; and Instituto Biosanitario de Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: San Miguel
authors.affiliation: Targeted Myeloma Treatment, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D014178:Translocation, Genetic